Short-term exercise improves beta-cell function and insulin resistance in older people with impaired glucose tolerance

BACKGROUND: There is a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Normal aging is associated with insulin resistance and impaired insulin secretion, with greater defects in people with IGT. Short-term exercise has been found to increase insulin sensitivity, but little is known about acute exercise effects on beta-cell function in older people with IGT. METHODS: We assessed the effects of 7 consecutive days of supervised aerobic exercise (1 h/d at 60-70% heart rate reserve) in 12 sedentary older people with IGT. Screening included oral glucose tolerance test, stress/maximal O(2) uptake test, and dual-energy x-ray absorptiometry scan. Participants had a frequently sampled iv glucose tolerance test at baseline and 15-20 h after the seventh exercise session. Insulin sensitivity (S(I)), glucose disappearance constant (Kg, a measure of iv glucose tolerance), acute insulin response to glucose (AIRg), and disposition index (AIRg x S(I)), a measure of beta-cell function in relation to insulin resistance, were calculated. RESULTS: Exercise was well tolerated. Body weight, fasting glucose, fasting insulin, and iv glucose tolerance were unchanged with exercise. S(I) increased by 59%, AIRg decreased by 12%, and disposition index increased by 31%. There was no significant change in fasting lipid, catecholamine, leptin, or adiponectin levels. CONCLUSIONS: Short-term exercise not only improved insulin resistance but also significantly enhanced beta-cell function in older people with IGT. These effects of short-term exercise on beta-cell function cannot be explained by changes in body weight or circulating levels of lipids, leptin, adiponectin, or catecholamines.     

Predominant role of reduced beta-cell sensitivity to glucose over insulin resistance in impaired glucose tolerance

Aims/hypothesis Impaired glucose tolerance (IGT) is an insulin-resistant state and a risk factor for Type 2 diabetes. The relative roles of insulin resistance and insulin deficiency in IGT have been disputed.Methods In 40 IGT subjects and 63 sex-, age-, and weight-matched controls with normal glucose tolerance (NGT), we measured (i) indices of insulin sensitivity of fasting glucose production (by tracer glucose) and glucose disposal (M value on a 240 pmol·min^–1·m^–2 insulin clamp) and (ii) indices of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) derived from model analysis (Am J Physiol 283:E1159–E1166, 2002) of the insulin secretory response (by C-peptide deconvolution) to oral glucose.Results In comparison with NGT, IGT were modestly insulin resistant (M=29±2 vs 35±2 µmol·min^–1·kg_FFM^–1, p=0.01); insulin sensitivity of glucose production also was reduced, in approximate proportion to M. Despite higher baseline insulin secretion rates, IGT was characterized by a 50% reduction in glucose sensitivity [53 (36) vs 102 (123) pmol·min^–1·m^–2·mM^–1, median (interquartile range), p=0.001] and impaired potentiation [1.6 (0.8) vs 2.0 (1.5) units, p<0.04] of insulin release, whereas rate sensitivity [1.15 (1.15) vs 1.38 (1.28) nmol·m^–2·mM^–1] was not significantly reduced. Glucose sensitivity made the single largest contribution (~50%) to the observed variability of glucose tolerance.Conclusion/interpretation In IGT the defect in glucose sensitivity of insulin release quantitatively predominates over insulin resistance in the genesis of the reduced tolerance to oral glucose.     

Expression profiles of the glucose-dependent insulinotropic peptide receptor and LHCGR in sporadic adrenocortical tumors

Glucose-dependent insulinotropic peptide receptor (GIPR) and LHCGR are G-protein-coupled receptors with a wide tissue expression pattern. Aberrant expression of these receptors has rarely been demonstrated in adult sporadic adrenocortical tumors with a lack of data on pediatric tumors. We quantified the GIPR and LHCGR expression in a large cohort of 55 patients (25 children and 30 adults) with functioning and non-functioning sporadic adrenocortical tumors. Thirty-eight tumors were classified as adenomas whereas 17 were carcinomas. GIPR and LHCGR expression were analyzed by real-time PCR and normal human pancreatic and testicular tissue samples were used as positive controls. Mean expression values were determined by fold increase in comparison with a normal adrenal pool. GIPR mRNA levels were significantly higher in adrenocortical carcinomas than in adenomas from both pediatric and adult groups. LHCGR expression was similar in both carcinomas and adenomas from the pediatric group but significantly lower in carcinomas than in adenomas from the adult group (median 0.06 and 2.3 respectively, P<0.001). GIPR was detected by immunohistochemistry in both pediatric and adult tumors. Staining and real-time PCR results correlated positively only when GIPR mRNA levels were increased at least two-fold in comparison with normal adrenal expression levels. In conclusion, GIPR overexpression was observed in pediatric and adult adrenocortical tumors and very low levels of LHCGR expression were found in all adult adrenocortical carcinomas.     

Rosiglitazone improves insulin sensitivity and glucose tolerance in subjects with impaired glucose tolerance

OBJECTIVE: This study was designed to evaluate the effects of rosiglitazone (ROS) on insulin sensitivity, beta-cell function, and glycaemic response to glucose challenge and meal in subjects with impaired glucose tolerance (IGT). METHODS: Thirty patients with IGT (ages between 30 and 75 years and BMI (body mass index) < or = 27 kg/m2) were randomly assigned to receive either placebo (n = 15) or ROS (4 mg/day) (n = 15). All participants underwent a 75-g oral glucose tolerance test (OGTT), meal test, and frequently sampled intravenous glucose tolerance test (FSIGT) before and after the 12-week treatment. RESULTS: After 12 weeks of ROS treatment, there were significant increases in total cholesterol (TC) (4.25 +/- 0.22 vs 4.80 +/- 0.17 mmol/l, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (1.25 +/- 0.07 vs 1.43 +/- 0.06 mmol/l, P < 0.05), and low-density lipoprotein cholesterol (LDL-C) (2.70 +/- 0.15 vs 3.37 +/- 0.17 mmol/l, P < 0.05) without changes in triglyceride concentration, TC/HDL-C and LDL-C/HDL-C ratio. Although the acute insulin response (AIR) to intravenous glucose and disposition index (measured as the ability of pancreatic beta-cell compensation in the presence of insulin resistance) remained unchanged, the insulin sensitivity (SI) and glucose effectiveness (SG) were remarkably elevated (0.38 +/- 0.06 vs 0.54 +/- 0.09 x 10(-5) min(-1)/pmol, P < 0.05; 0.017 +/- 0.002 vs 0.021 +/- 0.001 min(-1), P < 0.05, respectively) in the ROS group. The glucose, insulin, and c-peptide areas under curve (AUC) in response to OGTT and the glucose and insulin AUC during meal were significantly ameliorated in the ROS group. Five out of 15 (33%) and two out of 15 (13%) subjects treated with ROS and placebo, respectively, reversed to normal response during OGTT (P < 0.05). CONCLUSION: Rosiglitazone treatment significantly improved insulin resistance and reduced postchallenge glucose and insulin concentrations in patients with impaired glucose tolerance without remarkable effects on beta-cell secretory function.     

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Objective  The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods  Eight obese patients with type 2 diabetes with poor glycaemic control (HbA_1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results  Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2 (nmol/l) × (110 min)⁻¹ (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)⁻¹ (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]⁻¹). Conclusions  Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. ClinicalTrials.gov ID no.: NCT 00612950 Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.     

糖耐量受损者胰岛素敏感性及胰岛β细胞功能的研究

目的 研究糖耐量受损(IGT)者的胰岛素抵抗(IR)及胰岛β细胞功能变化。方法 选取正常糖耐量(NGT)、IGT、2型糖尿病(T2DM)者共34例，以高胰岛素正血糖钳夹技术测定IR，行静脉葡萄糖耐量试验评估胰岛β细胞分泌功能。结果 与NGT组相比，IGT组、T2DM组的IR显著升高；IGT组胰岛素第一时相分泌明显下降，空腹胰岛素(FIns)水平及第二时相分泌水平升高；T2DM组IR与IGT组处于同一水平，FIns较NGT组显著减少。结论 由NGT向IGT的演变过程中，IR和胰岛素分泌缺陷共同起作用。     

Impaired glucose tolerance and reduced beta-cell function in overweight Latino children with a positive family history for type 2 diabetes

The objective of this study was to examine relationships between impaired glucose tolerance (IGT) and body composition and insulin-related phenotypes in 150 overweight Latino children with a family history of type 2 diabetes. Glucose tolerance was assessed by an oral glucose challenge. Body composition was assessed by dual energy x-ray absorptiometry and magnetic resonance imaging. Insulin sensitivity, the acute insulin response, and the disposition index (DI), as an index of beta-cell function, were determined by an iv glucose tolerance test and compared between normal glucose-tolerant and IGT children. IGT was present in 28% of children, and was similar across obesity groups, but higher in children exposed to gestational diabetes mellitus (41% IGT). There were no significant differences in body composition, fat distribution, insulin sensitivity, or acute insulin response, but DI was significantly lower in IGT children by 16% (P < 0.02), and DI was inversely related to age. In conclusion, IGT is present in 28% of overweight Latino children with a family history of type 2 diabetes, is not influenced by obesity, is more prevalent in children exposed to gestational diabetes mellitus, and is related to poor beta-cell function, which shows signs of deterioration with age in this population.     

Impaired beta-cell function in the presence of reduced insulin sensitivity determines glucose tolerance status in acromegalic patients

OBJECTIVE: Abnormal glucose tolerance is often demonstrated in acromegalic patients. Although insulin resistance is a common feature of acromegaly, it remains unclear whether the extent of insulin resistance per se determines the abnormal glucose tolerance. In order to elucidate this issue, we investigated insulin sensitivity and beta-cell function in acromegalic patients. DESIGN: Twenty-four acromegalic patients were studied in comparison with 24 healthy control subjects. To estimate insulin sensitivity and beta-cell function, we used correct homeostasis model assessment (HOMA) model, a computer-solved model. We also investigated the effects of surgical success on both parameters. RESULTS: HOMA insulin sensitivity (HOMA-%S) in the acromegalic patients was 74 +/- 51 (SD)%, significantly lower than that in 24 healthy controls (144 +/- 49%). HOMA-%S in 12 normal glucose tolerance (NGT) patients was 54 +/- 31%, not significantly different from that in impaired glucose tolerance (IGT; n = 11) or diabetes mellitus (DM; n = 1) patients (93 +/- 60%). By contrast, HOMA beta-cell function (HOMA-%beta) in the NGT acromegalic patients was 163 +/- 67%, significantly higher than the IGT/DM acromegalic patients (89 +/- 34%) and the healthy controls (72 +/- 19%). In 11 patients who achieved complete normalization of GH excess after surgery, HOMA-%S significantly increased to control ranges (from 76 +/- 26 to 159 +/- 61%) within 2 weeks after the surgical success. CONCLUSIONS: We conclude that insulin sensitivity is reduced to a similar extent in acromegalic patients with normal glucose tolerance and those with impaired glucose tolerance or diabetes. Compensatory hyperfunction of beta-cells appears to counterbalance the reduced insulin sensitivity in the acromegalic patients with normal glucose tolerance but not in those with impaired glucose tolerance or diabetes.     

Increasing incidence of abnormal glucose tolerance in women with prior abnormal glucose tolerance during pregnancy: DIAGEST 2 study

Aims Mild blood glucose abnormalities during pregnancy may be linked to later glucose tolerance abnormalities or diabetes mellitus. Our aim was to determine the prevalence of diabetes mellitus (DM), impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) 6.75 years after delivery in women with differential blood glucose status during pregnancy. Methods We compared long‐term outcomes among control women (n = 221), women with abnormal glucose tolerance during pregnancy (AGT; n = 322) and women with gestational diabetes (GDM; n = 466) who participated in DIAGEST 1. Women were recruited from 15 public maternity units in France. Clinical parameters could be determined in 155 control, 220 AGT and 338 GDM subjects. Rates of DM, IGT, IFG and ‘Any Abnormality’ were compared between the groups (American Diabetes Association criteria). Results Adherence to follow‐up was 70.7%. Rates of DM, IGT and IFG were respectively 0.9% DM, 2.1% IGT and 3.6% IFG in the control group; rates in the AGT group were 6.3%, 11.3% and 6.3%. In GDM women, the rates of DM, IGT and IFG were, respectively, 18.0%, 13.4% and 8.5%. Predictors for DM were previous GDM, medical history of hypertension, age at delivery ≥ 33 years, family history of diabetes, fasting glucose during pregnancy ≥ 5.5 mmol/l and the severity of hyperglycaemia during pregnancy defined by the number of abnormal blood glucose values fasting, 1, 2 and 3 h during the glucose tolerance test at diagnosis of GDM. Conclusion This study has identified a high prevalence of glucose tolerance abnormalities after AGT during pregnancy. Compared with GDM women, women with AGT have an intermediate risk of later diabetes.     

Impaired beta-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance

The development of type 2 diabetes mellitus is characterized by both impaired beta-cell function and increasing insulin resistance. To clarify the roles of them in developing type 2 diabetes, we evaluated insulin resistance by HOMA-IR and insulin secretion by HOMA beta-cell in 453 Japanese subjects whose fasting plasma glucose (FPG) and HbA(1c) levels were within normal range. HOMA beta-cell was found to decrease in the over 30 years groups, while HOMA-IR increased with body mass index (BMI). To analyze the reserve capacity of insulin secretion and insulin sensitivity, the 67 of them, who underwent a standard oral glucose tolerance test and were diagnosed with normal glucose tolerance (NGT), were divided into four degrees of BMI age-adjusted to 50 years. They were compared for insulinogenic index and ISI composite proposed by Matsuda and DeFronzo across the range of BMI. ISI composite was significantly less in the highest BMI group, while insulin secretion did not increase in the higher BMI groups. The subjects with higher BMI had remarkably lower insulinogenic indices than those with lower BMI. These data suggest that insulin secretory reserve is insufficient to compensate for increased insulin resistance in Japanese people with NGT at about 50 years of age.     

醛固酮瘤患者中包括葡萄糖依赖性促胰岛素肽受体在内的若干异常受体对醛固酮分泌的调节

ACTH非依赖性大结节性肾上腺增生(AIMAH)和肾上腺皮质腺瘤可引起库欣综合征或雄激素过多,而这些病变组织中皮质醇的产生常由异常表达的数种G蛋白耦联受体(CPCRs)所调节.在原发性醛固酮增多症(原醛)中,虽则肾素和血管紧张素Ⅱ受到抑制,但对于醛同酮产生的调节机制大部分仍不清楚.     

Cardiovascular and pupillary light reflexes in subjects with abnormal glucose tolerance

It is well known that in diabetes mellitus autonomic neuropathy frequently develops. This is usually determined by the cardiovascular reflex. Furthermore, even in borderline cases that have not become overt diabetes, we have already reported the presence of autonomic neuropathy as assessed by the pupillary light reflex. However, a relationship between the impairments of the cardiovascular and pupillary light reflexes is not clear, especially in people with abnormal glucose tolerance. In the present study diabetics were divided into three groups according to the results of their cardiac beat-to-beat variation (BBV) tests and Schellong tests; group I had no abnormality of these cardiovascular reflexes, group II had abnormal BBV scores and normal Schellong test scores, and group III had abnormal responses to both tests. People with borderline diabetes (B-DM) were free from any impairment of their cardiovascular reflexes. We examined their pupillary light reflexes. Age-matched non-diabetics were also studied as a control. The following results were obtained. (1) Compared to controls, (a) diabetics, but not borderline diabetics, had smaller pupils before photic stimulation (A1) and lower maximum dilatation velocities (VD). These illustrate sympathetic function; (b) diabetics and borderline diabetics had lower amplitudes of constriction (A3) and maximum constriction velocities (VC). These illustrate parasympathetic function; (c) borderline diabetics and those diabetics belonging to group III experienced a lower pupillary constriction rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of glucose-dependent insulinotropic polypeptide infused at physiological concentrations in normal subjects and Type 2 (non-insulin-dependent) diabetic patients on glucose tolerance and B-cell secretion

Summary The effects of porcine glucose-dependent insulinotropic polypeptide given by continuous intravenous infusion in normal subjects (n=6) and Type 2 (non-insulin-dependent) diabetic patients (n=6) have been investigated. The subjects were studied on 2 separate days after overnight fasts. On each day 25 g of glucose was infused from 0–30 min plus an infusion of either porcine glucose-dependent insulinotropic polypeptide (0.75 pmol·kg^–1·min^–1) or control solution. During the glucose-dependent insulinotropic polypeptide infusion plasma glucose values were reduced in normal subjects from 30–60 min (p<0.01) and in Type 2 diabetic patients at 45 and 60 min (p<0.05). In the normal subjects insulin concentrations were greater from 10–35 min (p<0.01) following glucose-dependent insulinotropic polypeptide infusion and peak values were increased by 123%. In the Type 2 diabetic patients following glucose-dependent insulinotropic polypeptide infusion insulin levels were increased from 4–40 min (p<0.01) but peak values were only increased by 27%. In the normal subjects C-peptide values were greater from 25–45 min (p<0.01) following glucose-dependent insulinotropic polypeptide infusion and peak C-peptide levels were increased by 82%. In the Type 2 diabetic patients following the glucose-dependent insulinotropic polypeptide infusion C-peptide levels were increased from 6–55 min (p<0.01) and peak values were increased by 20%. Plasma glucose-dependent insulinotropic polypeptide levels were within the physiological post prandial range during the glucose-dependent insulinotropic polypeptide infusion. Glucose-dependent insulinotropic polypeptide is insulinotropic in normal subjects and Type 2 diabetic patients at physiological concentrations and results in improved glucose tolerance. This insulinotropic effect is less marked in the diabetic patients and may represent insensitivity of the B cell to glucose-dependent insulinotropic polypeptide.     

Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance.

AIMS: To determine the effects of rosiglitazone on insulin sensitivity, glucose tolerance and ambulatory blood pressure when administered to subjects with persistent impaired glucose tolerance (IGT). METHODS: Eighteen subjects with persistent IGT were randomized to receive rosiglitazone 4 mg twice daily or matching placebo for 12 weeks. Evaluation at baseline and at the end of treatment included measurement of whole body insulin sensitivity during a euglycaemic hyperinsulinaemic clamp and deriving an insulin sensitivity index. Changes in glucose and insulin concentration were determined after oral glucose tolerance test (OGTT) and mixed meal tolerance tests, and 24-h ambulatory blood pressure was monitored. RESULTS: Rosiglitazone significantly improved the insulin sensitivity index by 2.26 micro g/kg per min per pmol/l relative to placebo (P = 0.0003). Four of nine subjects receiving rosiglitazone reverted to normal glucose tolerance and 5/9 remained IGT, although four of these had improved 2-h glucose values. In the placebo group, 1/9 subjects progressed to Type 2 diabetes and 8/9 remained IGT. Following OGTT and meal tolerance test, glucose and insulin area under curve were reduced over 3 and 4 h, respectively. Compared with placebo, ambulatory blood pressure decreased significantly in the rosiglitazone group by 10 mmHg systolic (P = 0.0066) and 8 mmHg diastolic (P = 0.0126). CONCLUSIONS: Consistent with its effects in patients with Type 2 diabetes, rosiglitazone substantially improved whole body insulin sensitivity and the glycaemic and insulinaemic responses to an OGTT and meal tolerance test in subjects with persistent IGT. Furthermore, rosiglitazone reduced systolic and diastolic ambulatory blood pressure in these subjects.     

Acarbose improves fibrinolytic activity in patients with impaired glucose tolerance

Acarbose has been shown to ameliorate insulinemia, suggesting that it may exert favorable effects on the impaired fibrinolytic state in prediabetic patients. We therefore conducted a randomized controlled study to examine the effects of acarbose on fibrinolysis in patients with impaired glucose tolerance (IGT). The participants were randomized to receive (n = 20) or not (control, n = 20) 100 mg of acarbose before each meal (300 mg/d) for 3 months. A marked decrease in the plasma levels of plasminogen activator inhibitor 1 (by 42%) and fibrinogen (by 27%) was observed in the acarbose group at the end of the study, whereas no significant changes in the levels of these parameters were observed in the control group. We also conducted postprandial evaluation of insulin-related clinical markers and found ameliorated hyperinsulinemia in the subjects treated with acarbose. These results indicate that acarbose could improve fibrinolysis in patients with IGT, mainly by ameliorating insulinemia. Other favorable effects of acarbose, such as reduction in the plasma levels of oxidized low-density lipoprotein, glucose toxicity, and hyperglycemia, might also contribute, at least in part, to the beneficial effects of the drug on the fibrinolytic state in patients with IGT.     

Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome

Insulin resistance is common in adults with polycystic ovary syndrome (PCOS). Although recent data demonstrate that insulin resistance is present in the early stages of PCOS, the prevalence of insulin resistance in adolescents with PCOS has not been determined. Likewise, the prevalence of impaired glucose tolerance (IGT) or type 2 diabetes mellitus (DM) in adolescent cohorts has not been established. In this study we sought to obtain preliminary data regarding the prevalence of IGT and DM in adolescents with PCOS and to assess the ability of screening tests to predict these abnormalities within this population. Twenty-seven adolescents with PCOS underwent oral glucose tolerance tests. Plasma glucose and insulin levels were obtained at baseline, and glucose was measured 2 h after a 75-g glucose challenge. The 2-h plasma glucose level was used to categorize subjects as having IGT or the provisional diagnosis of DM. Eight of our 27 subjects had IGT, and 1 had previously undiagnosed DM. These abnormalities were seen among lean and obese subjects. Fasting plasma glucose levels and simple measures of insulin resistance were suboptimal predictors of IGT and DM within our cohort. As in adults, our results indicate that adolescents with PCOS are at increased risk for IGT and DM and that the 2-h plasma glucose level after an oral glucose challenge appears to be the most reliable screening test for these abnormalities. Our results need to be corroborated by future studies that determine the prevalence of abnormalities in glucose tolerance among large populations of adolescents, both with and without PCOS. However, as DM may be preventable by lifestyle modifications, we would recommend that adolescents with PCOS undergo periodic screening for abnormal glucose tolerance using 2-h postchallenge plasma glucose levels.